JPH0780898B2 - Antiviral nucleoside - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to pharmaceutically acceptable 5'-salts or esters of 3'-azido-3'-deoxythymidine and their use in the treatment or prevention of human retroviral infections. is there.

A retrovirus must first replicate its genome before it can be replicated.
It forms a subgroup of RNA viruses that must undergo "reverse transcription" of RNA into DNA ("transcription" is traditionally referred to as the synthesis of RNA from DNA). Once this DNA is formed, the viral genome becomes integrated into the host's cell genome, making full use of the host cell's transcription / translation machinery for replication purposes. Once integrated, the viral DNA is virtually indistinguishable from the host DNA, and the virus can remain in this state and survive for the life of the cell. The virus in this state is invulnerable to attack, so whatever process it takes, it must be directed to another state of the life cycle, thus:
It must be continued until all virus-bearing cells die.

Both HTLV-I and HTLV-II are retroviruses and are known to be responsible for human leukemia. HTLV-I infections are particularly widespread, causing a large number of deaths worldwide each year.

Retroviral species are now already reproducibly isolated from patients with AIDS. The characteristics of the retrovirus are widely known, but at present there is no consistent name as a virus, and recently, human T-cell lymphotropic virus III (HTLVIII), AIDS-related retrovirus (ARV), It is called lymphadenopathy-related virus (LAV). Acquired immunodeficiency virus (AIDV) is expected as the name to be agreed internationally. This virus (hereinafter referred to as AIDV) was found to preferentially infect and destroy OKT ⁴ surface-labeled T cells, and at present, AIDS is recognized as the etiology. The patient progressively loses this group of T cells, reverses the immune system's overall balance, diminishes the ability to fight other infections, and makes the patient susceptible to opportunistic infections, often determined to be incurable. Thus, the death of AIDS victims is usually due to opportunistic infections such as pneumonia and virus-induced cancers.
It is not a direct result of the infection.

Recently, AIDV has also been recovered from other types of tissues, such as B cells expressing T ⁴ markers, macrophages, and tissues not related to blood of the central nervous system (CNS). This latter infection has been found in patients with classic AIDS symptoms and is associated with progressive demyelination, such as weakness, brain disease, progressive dysarthria, ataxia, and disorientation. I have symptoms.

There are at least four clinical manifestations of AIDV infection. The only indication of infection in the original "carrier" condition is the presence of anti-AIDV antibodies in the bloodstream. It is believed that such a "carrier" can become infected by, for example, blood transfusion, sexual intercourse, or the used injection needle. This carrier condition often does not transition to the second stage, which is characterized by persistent generalized lymphadenopathy (PGL). It has recently been estimated that about 20% of patients with PGL go into a more advanced situation called the "AIDS-related syndrome" (ARC). Physical symptoms associated with ARC include general discomfort, elevated body temperature, and chronic infection. This condition normally progresses to the final lethal AIDS condition, which results in the patient's total loss of ability to fight the infection.

These retroviruses and others have only recently been identified, and the diseases they relate to are inherently life-threatening, so it is imperative to develop strategies to combat these viruses. ing.

Currently, various drugs have been proposed as "therapeutic agents" for AIDS. Drugs include antimonio tungustate, suramin, ribavirin, isoprinosine, etc., which are slightly toxic or do not show significant antiretroviral activity. Upon infection, the AIDV genome is incorporated into the DNA of the host cell, and in this state it cannot be damaged by attack, so it survives as long as the host cell survives, causing a new infection.
For this reason, any treatment for AIDS must be long-term, and perhaps life-long, and therefore the treated substance must be toxicologically acceptable. The report describes testing compounds against various retroviruses, such as the murine retrovirus Friend leukemia virus (FLV). For example, Krieg et al. (Experimental Cell Research, Exp. Cell Res., 116 (1978), 21-29)
Found in an in vitro experiment that 3-azido-3'-deoxythymidine was active against FLV, and was published by Ostertag et al. (Procedures of National Academy of Sciences (Proc. .N
at.Acad.sci.) (1974), 71, 4980-85), based on the lack of FLV-related antiviral activity and cytotoxicity.
Azido-3-deoxythymidine states that "it could be an advantageous alternative to bromodeoxyuridine for the medical treatment of diseases caused by DNA viruses." However, De Clerq et al. (Biochem.Pharm.) (1980), 29, 1849
-1851), and 6 years later, 3'-azido-3'-deoxythymidine was much more active in their test against any virus used, including cowpox, HSVI, and varicella virus (VZV). It is concluded that it has not been shown.

Glinski et al (J.Org.Chem.) 1973, 38, 429
9-4305) discloses certain derivatives of 3'-azido-3'-deoxythymidine (below) and their ability to inhibit mammalian exoribonuclease activity.

The present inventors have now shown that 3'-azido-3'-deoxythymidine has a surprisingly active ability against human retroviruses, and especially for AIDV, high utilization as shown in the experimental data cited below. Was found to show. By virtue of this activity, the compound is considered therapeutically useful for human retroviral infection.

According to a first aspect of the invention, a compound of formula (I) (ie 3'-azido-3'-deoxythymidine), or a pharmaceutically acceptable 5'-salt or ester thereof, is used for the treatment of human retroviral infections. Alternatively, it is proposed as a compound used for prevention.

Compounds of formula (I) and their pharmaceutically acceptable 5 '
The salt or ester is referred to below as the compound according to the invention.

The activity of 3'-azido-3-deoxythymidine against human retrovirus was confirmed by various in vitro assay systems. For example, infection of the H9 human lymphoblastoid cell line with AIDV resulted in 0.
Application of 3'-azido-3'-deoxythymidine at low concentrations of 013 mcg / ml is effectively prevented. AIDV infection of U937 human lymphoblastoid cells, PHA-stimulated leukocytes, and cultured peripheral blood lymphocytes is also prevented at similar low concentrations. Also, up to 5000 AIDV virions per cell and cloned T4 using tetanus-specific T-velper lymphocytes,
In the 10-day administration experiment, the number of cells treated with 3'-azido-3-deoxythymidine did not decrease, whereas the number of untreated cells decreased to 1/5. Transformed with HTLV-I and
The cytopathic effect in the same cell line superinfected with IDV was also completely blocked.

Other studies using AIDV reverse transcriptase revealed that the activity of this enzyme was blocked by the 3'-azido-3'-deoxythymidine triphosphate by a competitive inhibitory mechanism.

Phase I clinical trials have shown that 3'-azido-3'-
Deoxythymidine was found to be capable of crossing the blood / brain barrier in clinically effective amounts. This property is unusual and valuable for the treatment and prevention of CNS infections caused by human retroviruses. 3'-Azido-3'-corrects retrovirus-induced harm
The capacity of deoxythymidine has been demonstrated in a mouse model. In this model, administration of 3'-azido-3'-deoxythymidine prevented splenomegaly due to intravenous administration of leukemia virus in Rausier mouse, the corresponding virus in HTLV mice. Further detailed experiments showed that 3'-azido-3'-deoxythymidine was found to be less than 0.
It was also found that a low concentration of 8 mcg / ml suppressed the in vitro replication of HTLV-I.

Thus, in a more particular and preferred aspect of the invention, it is proposed to use the compounds according to the invention for the manufacture of a medicament for the treatment and prevention of human retroviral infections.

The invention further provides a method for the treatment or prevention of AIDS in a patient, which comprises administering to the patient an effective amount of a compound according to the invention.

The invention also includes a method of treating or preventing a retrovirus-induced infection in a patient, which comprises administering to the patient an effective antiviral amount of a compound according to the invention.

Further according to the invention there is also provided a compound according to the invention for use in the treatment or prophylaxis of an AIDS or viral infection as defined above. Examples of human retroviral infections that can be treated or prevented according to the present invention include T cell lymphotropic retrovirus (HTLV), particularly HTLV-I, HTLV-II.
And AIDV (HTLV-III). Clinical situations that can be treated or prevented according to the present invention include AIDS, AIDS-related syndromes, and HTLV-I positive leukemias and lymphomas. AIDV, AIDV-CNS infection, PGL
And patients with antibodies to ARC.

"Pharmaceutically acceptable 5'-salt or ester" means that when administered to a patient, it may result in a metabolite active against 3'-azido-3'-deoxythymidine, or an antiretrovirus thereof. Includes all corresponding compounds.

Preferred esters of the compounds of formula (I) are esters of carboxylic acids in which the ester group other than carbonyl is a straight or branched chain alkyl, alkoxyalkyl (eg methoxymethyl), aralkyl (eg benzyl). , Aryloxyalkyl (eg phenoxymethyl), aryl (eg phenyl optionally substituted with halogen, C _1-4 alkyl, or C _1-4 alkoxy); sulfonic acids such as alkyl- or aralkylsulfonyl (methanesulfonyl) Esters; and mono-, di- or triphosphates. For the above esters, the alkyl moiety present in the ester should have 1-18 carbon atoms, especially 1-4 carbon atoms, unless otherwise specified. The aryl moiety present in the ester preferably comprises a phenyl group. Also, reference to any of the above compounds includes reference to pharmaceutically acceptable salts thereof.

Experiments have shown that 3'-azido-3'-deoxythymidine is converted in vitro by cellular enzymes to 5'-monophosphate. Monophosphate is then phosphorylated by other enzymes to form triphosphate via diphosphate. Other studies suggest that an effective chain terminator in reverse transcription of AIDV may be demonstrated by its effect on avian myeloblastosis virus and Moloney murine leukemia virus. It has been demonstrated to be the triphosphate form of 3'-azido-3'-deoxythymidine. This form also suppresses AIDV reverse transcriptase in vitro, but its effect on the activity of human DNA polymerase is almost negligible.

Compounds of formula (I) and their pharmaceutically acceptable 5'-
Examples of salts include, for example, alkali metal (eg sodium), alkaline earth metal (eg magnesium) salts, ammonium, and a suitable base such as ▲ NX ⁺ ₄ ▼ (X is C _1-4 alkyl). Salts of bases derived from

Accordingly, the invention further provides the following 5'-esters: monophosphate, disodium monophosphate,
As a novel pharmaceutical agent, which is a pharmaceutically acceptable 5'-salt or ester of 3'-azido-3'-deoxythymidine other than 2-cyanoethyl monophosphate, triphosphate, p-toluene sulfonate, acetate and methanesulfonate. Provide useful compounds.

Particular examples of the pharmaceutically acceptable 5'-salts or esters of the compounds of formula (I) which can be used according to the invention include the monosodium salt and the following 5'-esters, monophosphine: Ate, disodium monophosphate, diphosphate, triphosphate, acetate,
There are 3-methyl-butyrate, octanoate, palmitate, 3-chlorobenzoate, benzoate, 4-methylbenzoate, hydrogen succinate, pivalate, and mesylate.

3'-azido-3'-deoxythymidine or a pharmaceutically acceptable 5'-salt or ester (hereinafter referred to as active ingredient) is used in humans for oral or anal administration for the prevention or treatment of retroviral infection. , Nasal, topical (including buccal, sublingual), vaginal, parenteral (including subcutaneous, intramuscular, intravenous, intradermal) and the like. The preferred route is the condition and age of the recipient, the nature of the infection,
And the different active ingredients selected.

Generally, a suitable dose is 6-90 mg, most preferably 15-60 mg, per unit weight (Kg) of patient per day. The desired dose is preferably given in two, three, four, five, six or more divided doses at appropriate intervals during the day. These sub-doses are in the form of unit doses (e.g. 10-1500 mg, preferably 20-1000 m
g, most preferably 50-700 mg of active ingredient is included per unit dosage form). From experiments with 3'-azido-3'-deoxythymidine, administration was carried out such that the plasma concentration of active compound was from about 1 to about 75 μM, preferably about 2.
It is presumed that it is best to reach a peak of -50 μM, most preferably about 3 to about 30 μM. This administration is carried out, for example, by dissolving the active ingredient in saline optionally to obtain 0.1-5%.
Intravenous injection as a solution of
Oral administration may be performed as a large pill containing about 100 mg / Kg. A desirable blood concentration is about 1 hour
Continuous infusion to give 0.01-about 5.0 mg / Kg can be maintained by intermittent infusion containing about 0.4-about 15 mg / Kg of active ingredient.

If it is not possible to administer the active ingredient alone, it is preferable to present it as a pharmaceutical formulation. The formulation according to the invention comprises at least one active ingredient as defined above, which is
With one or more acceptable carriers, and optionally other therapeutic agents. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Formulations include those suitable for oral, anal, nasal, topical (including buccal, sublingual), vaginal or parenteral (including subcutaneous, intravenous, intramuscular, intradermal) administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include adding 1
Means for integrating with the carrier which constitutes the seed or two adjunct ingredients are also included. In general, the formulation is a liquid carrier of the active ingredient,
Or evenly with a finely divided solid carrier, or both,
And intimately integrated and, if desired, shaped by shaping the product.

Formulations of the present invention, suitable for oral administration, may be capsules, capsules, tablets or the like containing a predetermined amount of the active ingredient, as separate units, as a powder or granules, an aqueous or non-aqueous solution or suspension. Or as an oil-in-water or water-in-oil emulsion. The active ingredient may also be presented as a bolus, lick or paste. Oral seasonings further include sweeteners, flavoring agents,
Other materials known to the art such as thickeners may be included.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are powders, granules and other active ingredients in a fluid form, binder (eg povidone, gelatin, hydroxymethyl cellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium glycolate starch, cross-linked). Povidone, cross-linked sodium carboxymethyl cellulose), surfactants, or dispersants can be optionally mixed and prepared by compression on a suitable machine. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. Tablets can be coated as desired,
It may be scored and formulated, for example, with a variable amount of hydroxypyropyrmethylcellulose to provide a slow and constant release of the active ingredient.

Formulations suitable for topical administration in the mouth include flavored bases,
Usually, sucrose containing active ingredients in sucrose and acacia tragacanth; troches containing active ingredients in an inert base such as gelatin and glycerin or sucrose and acacia; active ingredients in a suitable liquid carrier. There is a mouthwash that contains.

Formulations for anal administration may be presented as suppositories with a suitable base including, for example, cocoa butter or a salicylate agent.

Formulations suitable for buccal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous or non-aqueous isotonic sterile solutions which may include antioxidants, buffers, bacteriostats, and solutes that make the formulation isotonic with the blood of the intended recipient. Injectables; sterile aqueous or non-aqueous suspensions which may contain suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, such that a sterile liquid carrier, such as water for injection, may be added just prior to use. It can be stored in the freeze-dried state. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, tablets and the like as described above.

Preferred unit dosage formulations are those containing a daily dose or unit dose of the active ingredient; a daily sub-dose; or an appropriate fraction thereof.

The component to be administered is, for example, 9-[[2-hydroxy-1-
(Hydroxymethyl) ethoxy] methyl] guanine, 2
Such as-(hydroxyethoxymethyl) guanine [acyclovir], 2-amino-9- (2-hydroxyethoxymethyl) purine, interferon (eg, α-interferon), interleukin II, and phosphonoformate [foscarnet]. Can be used in combination with other medications, or with bone marrow or lymphocyte transplants, or with drugs such as levamisole and thymosin that help to appropriately increase the number and / or function of lymphocytes. .

It should be understood that the formulations of the present invention may include, in addition to the components specified above, other materials known to those of ordinary skill in the art.

Compounds of formula (I) and their pharmaceutically acceptable 5 '
-The salts or esters can be prepared by conventional methods, such as those described in the following references, or by analogy therewith: JR, Horwitz et al., Journal. Of Organic Chemistry (J.Org.Chem), 29 (July 1964), 20
76-78; M. Imazawa et al.
Of Organic Chemistry, 43 (15) (197
8), 3044-3048; KA Watanab
e) and others, Journal of Organic Chemistry, 45, 3274 (1980); and RPGlinski, Journal of Chemical Society Chemical Communication (J. Chem. So.
c. Chem. Commun., 915 (1970), as well as the methods described in the Examples.

The present invention further includes a method of preparing a compound of formula (I) and a pharmaceutically acceptable 5'-salt or ester thereof, which comprises the following reaction: (A) The following compound, wherein M is Reacting a 3'-azido group precursor), or a derivative thereof (eg, an ester or salt), with or under conditions that aid in the conversion of the precursor group to the desired azido group. thing, (B) a compound of the formula: where R represents a hydroxyl group, or a precursor of a pharmaceutically acceptable group thereof, together with an agent that aids in the conversion of the precursor group to the corresponding desired group, or Reacting under conditions, (C) reacting a compound of the following formula, or a functionally equivalent compound thereof, with a compound that serves to introduce the desired ribofuranosyl ring to the 1-position of the compound of formula (IV), or (D) reacting a compound of the following formula (wherein R ¹ is a hydroxyl group, or R as defined above) with or under conditions to a reagent which aids in the conversion of said compound to a compound according to the invention. ,
And at the same time or thereafter, one or two of the following conversions
Optionally: (i) When the 3'-azido-3'-deoxythymidine is formed, converting the compound to its pharmaceutically acceptable 5'-salt or ester.

(Ii) When a 3'-azido-3'-deoxythymidine pharmaceutically acceptable 5'-salt or ester thereof is formed, the derivative is converted to a compound of formula (I), or another derivative thereof. To convert.

In the above method of the invention, the materials and conditions as well as the precursor compounds of formulas (II) and (III) are
It is estimated to be selected from those known in the art of nucleoside synthetic chemistry. Examples of such conversion procedures are given below as a guide, but it should be understood that they may be modified in a conventional manner depending on the desired compound of formula (I). In particular, if the conversion is described to result in the undesired reaction of an otherwise labile group, the group is protected in a conventional manner and the protective group removed after the conversion is complete. be able to. Thus, in method (A), the group M of the compound of formula (II) may be, for example, halogen (eg chlorine), hydroxy, or organic sulfonyloxy (eg trifluoromethylsulfonyloxy, methanesulfonyloxy, or p-toluenesulfonyl). Represents the group of oxy).

In the preparation of compounds of formula (I) such that the group M is a halogen (eg chlorine) in the threo configuration (the 5'-hydroxy group is advantageously protected eg by a trityl group). The compound of formula (II) can be treated with, for example, lithium azide or sodium azide.
The starting material for the 3'-threo-halogen (eg chlorine) is
For example, it can be obtained by reacting the corresponding 3'-erythro-hydroxy compound with, for example, triphenylphosphine and carbon tetrachloride, or by treatment with an organic sulfonyl halide (eg trifluoromethanesulfonyl chloride), Corresponding 3'-er
The ythro-organosulfonyloxy compound is formed and subsequently halogenated. In addition, 3'-threo of the formula (II)
The -hydroxy compound can be treated, for example, with triphenylphosphine, carbon tetrabromide and lithium azide to form the corresponding 3'-erythro azide compound. Then any protecting groups can be removed, for example as described above. With regard to the method of (B), R is a protected hydroxyl group, for example an ester group of the type cited above in connection with formula (I), in particular acetoxy, or an ether group such as a trialkylsilyloxy group, Eg te
rt-Butyldimethylsilyloxy or an aralkoxy group, for example triphenylmethoxy. Such a group can be converted, for example, by hydrolysis to the desired hydroxyl group or by transesterification to another ester group of 3'-azido-3'-deoxythymidine.

With regard to the method of (C), this means that for example
Of a suitable pyrimidine, or a salt or protected derivative thereof, with a compound of the formula :, followed by removal of any protecting groups.

(Wherein A is, for example, acetoxy, or benzoyloxy, or halogen (for example, chlorine), and B is an optionally protected group (for example, p-toluenesulfonyloxy group).) Regarding the method of (D) Is R ¹ is R in formula (III)
Is a precursor group as described above. The 3'-azido-3'-deoxythymidine is then moistened, for example, by reaction with an alkali metal azide (eg lithium azide).
It can be conveniently obtained in a suitable solvent such as DMF and then, under mild conditions, advantageously hydrolyzed by an acid or base.

The 3'-azido-3'-deoxythymidine, phosphorylation agent, for example POCl _3, or a suitable esterifying agent, can tolerate example Yotsute the reaction with an acid halide or acid anhydride, in each pharmaceutical, phosphates, Or it can be converted to other esters. The compounds of formula (I), including their esters, can be converted into their pharmaceutically acceptable salts in a conventional manner, eg by treatment with a suitable base. The ester or salt of 3'-azido-3'-deoxythymidine can be converted to the original compound by, for example, hydrolysis.

Examples will be given below, but these are merely intended to exemplify the effects of the present invention, and are not intended to limit the scope of application of the present invention. The term "active ingredient" as used in the examples means a compound of formula (I), or a pharmaceutically acceptable 5'-salt or ester thereof.

Example 1: Tablet formulation The following formulations A and B were prepared by wet granulating the ingredients with a solution of Povidone and then adding magnesium stearate and pressing.

Formulation A mg / tablet mg / tablet (a) Active ingredient 250 250 (b) Lactose BP 210 26 (c) Povidone BP 159 (d) Sodium glycolate starch 20 12 (e) Magnesium stearate 5 3 500 300 Formulation B mg / tablet mg / tablet (a) Active ingredient 250 250 (b) Lactose 150- (c) Avicel PH 101 60 26 (d) Povidone BP 159 (e) Sodium glycolate starch 20 1
2 (e) Magnesium stearate 5 3 500 300 formulation C mg / tablet (a) Active ingredient 100 (b) Lactose 200 (c) Starch 50 (d) Povidone 5 (e) Magnesium stearate 4 359 The following formulation D and E was prepared by direct compression of the mixed ingredients. The lactose used in formulation E was a direct compression type (Deairy Crest- "Zeparox" (Dairy Cr
est- "Zeparox"). Formulation D mg / capsule active ingredient 250 Pregelatin treated starch NF15 150 400 formulation E mg / capsule active ingredient 250 Lactose 150 Avicel 100 500 Formulation F (control release formulation) mg / capsule This formulation contains the following ingredients in povidone solution It was prepared by wet granulation, adding magnesium stearate and compressing.

mg / tablet (a) Active ingredient 500 (b) Hydroxypyropyrcellulose (Methocel K4M Premium) 112 (c) Lactose BP 53 (d) Povidone BPC 28 (e) Magnesium stearate 7 700 Drug release It occurred over about 6-8 hours and was complete after 12 hours.

Example 2: Capsule Formulation Formulation A Formulation was prepared by mixing the ingredients of Formulation D from the above example and filling into a two-part hard gelatin capsule. Formulation B (below) was similarly prepared.

Formulation B mg / capsule (a) Active ingredient 250 (b) Lactose BP 143 (c) Sodium glycolate starch 25 (d) Magnesium stearate 2 420 Formulation C mg / capsule (a) Active ingredient 250 (b) Macrogol (Macrogol) 4000 BP 350 600 capsules were prepared by melting Macrogol 4000BP, dispersing the active ingredient in the melt, and filling the melt in a two-part hard gelatin capsule. Formulation D mg / capsule Active ingredient 250 Lecithin 100 Peanut oil 100 450 Capsules were prepared by dispersing the active ingredient in lecithin and peanut oil and filling the dispersion in soft gelatin capsules.

Formulation F (Control Release Capsule) Next, a control release capsule formulation was prepared by extruding components (a), (b) and (c) using an extruder, then spheronizing and drying. The dried pellets were coated with a controlled release membrane (d) and filled into two-part hard gelatin capsules.

mg / capsule (a) Active ingredient 250 (b) Microcrystalline cellulose 125 (c) Lactose BP 125 (d) Ethylcellulose 13 513 Example 3: Formulation for injection Formulation A Active ingredient 200 g 0.1M hydrochloric acid solution pH4.0-7.0 Adjust to 0.1M sodium hydroxide solution pH 4.0-7.0 Dilute in 10 ml of sterilized water Dissolve the active ingredient in most of the water at 35 ° -40 ° C and adjust the pH to 4.0-7.0 with an appropriate amount of hydrochloric acid or sodium hydroxide. It was adjusted.
The volume was adjusted to 10 ml by adding water, filtered through a sterilized micropore filter, placed in a sterilized amber glass bottle (Type 1, 10 ml), sealed with a sterilizer, and double-sealed.

Formulation B Active ingredient 0.125g Diluted in sterile, pyrogen-free pH7 buffer 10ml Example 4: Intramuscular injection solution Active substance 0.20g Benzyl alcohol 0.10g Glycofurol 75 1.45g Injection water 3.00ml in water Dilution The active ingredient was dissolved in glycofurol, benzyl alcohol was added to dissolve it, and then water was added to make 3 ml. The mixture was filtered through a sterile micropore filter and sealed in sterile amber glass bottles (Type 1, 3 ml).

Example 5: Syrup Active ingredient 0.2500 g Sorbitol solution 1.5000 g Glycerin 2.0000 g Sodium benzoate 0.0050 g Fragrance, Peach 17.42.3169 0.0125 ml Diluted in purified water 5.0000 ml Active ingredient, glycerin and most of the purified water The resulting mixture was dissolved in a mixture with and the solution of sodium benzoate was added to the solution. Purified water was added to bring the total volume to 5 ml and mixed well.

Example 6: Suppository mg / suppository Active ingredient (63 μm) ^* 250 Hard fat, BP (Danamit Nobel-Witepsol
H15 (Dynamit Nobel-Witepsol H15) 1770 2020 ^{* The} active ingredient was used as a powder in which at least 90% of the particles had a particle size of 63 μm or less.

One-fifth of the hard fat was melted in a pan with a steam outer casing at a maximum of 45 ° C. The active ingredients were sifted through a 200 μm sieve, added to the melt base and mixed and mixed using a silverson with a cutter until a smooth dispersion was obtained. The remaining hard fat was added to the suspension and stirred while keeping the mixture at 45 ° C. to obtain a uniform mixture. 250 total suspension
After filtering through a stainless steel sieve of μm, while stirring,
It was left to cool to 40 ° C. At 38 ° -40 ° C, 2.02 g of the mixture was filled into a suitable plastic mold (2 ml) and allowed to cool to room temperature to form a suppository.

Example 7: Petsalry mg / petsalley active ingredient (63 μm) 250 anhydrous dextrose 380 potato starch powder 363 magnesium stearate 7 1000 The above ingredients were directly mixed and the mixture was directly compressed to prepare a pessary.

Example 8 3'-Azido-3'-deoxy-5'-O-
Octanoyl thymidine Octanoyl chloride (1.2 eq) was added to a solution of 3'-azido-3'-deoxythymidine in pyridine (0 ° C). The reaction was allowed to proceed by raising the temperature to room temperature. tl
Upon completion of the reaction indicated by c (CHCI ₃ : MeOH; 20: 1 on silica gel), the solution was poured onto ice water and the resulting aqueous phase decanted. The oil phase silica gel CHCI _3: was subjected to elution chromatography MeOH. The title compound was obtained as an oil after evaporation of the solvent from the appropriate fractions.

CHN: Calculated composition-C: 54.95, H: 6.92, N: 17.80: Measured composition-C:
54.82, H: 6.96, N: 17.66.

δ7.46 (d, 1H, J _5,6 = 1Hz, 6H), δ6.13 (t, 1H, 1'H), δ4.5-4.2 (m, 3H, 3'H, 5'CH ₂ ) δ4.0-3.8 (m, 1H, 4'H) δ2.3-2.1 (m, 4H, 2'H, octanoyl (CH ₂ ) 1), δ
_{1.81 (d, 3H, J 5,6} = 1.0Hz, 5CH 3), δ1.5-0.6 (m, 13H, 5 ' octanoyl (CH _{2) 5} CH ₃₎ Example 9 5'-acetyl-3'- Azido-3'-deoxythymidine To a solution of 3'-azido-3'-deoxythymidine (20 g) in pyridine (50 ml) was added acetyl chloride (2.1 eq) at room temperature. The mixture was stirred for 2 hours for reaction, allowed to stand at 0-5 ° C for 20 hours, poured into ice water while stirring, and the aqueous phase was decanted. The oily product was dissolved in water, extracted with water (5x), 0.5N hydrochloric acid, water (2x) and dried over magnesium sulfate. The solution was filtered and subjected to vacuum evaporation. The residual oil was dissolved in chloroform, applied to a silica gel column and separated by flash chromatography using a 2% solution of methanol in chloroform. The fraction containing the product was evaporated, and the oil was mixed again with an ethyl acetate / hexane mixture (volume ratio).
6: 4) and chromatographed. The product containing fraction was vacuum evaporated to give a white solid.

Melting point 96-98 ° C.

Calculated-C: 46.60, H: 4.89, N: 22.65.

Found -C: 46.67, H: 4.94, N: 22.59.

Example 10 The following compounds were prepared from the appropriate acid halide or anhydride according to the procedure of Example 8 or 9.

3'-Azido-5'-O-benzoyl-3'-deoxythymidine Calculated-C: 53.68, H: 4.77, N: 18.41.

Found -C: 53.61, H: 4.72, N: 18.46.

Melting point 54-59 [deg.] C.

3'-Azido-3'-deoxy-5-O-hivaloylthymidine calcd-C: 51.27, H: 6.03, N: 19.93.

Found -C: 51.07, H: 6.05, N: 19.83.

Melting point 99-100 ° C.

3'-Azido-3'-deoxy-5'-O- (3-methylbutyryl) thymidine Calculated-C: 50.24, H: 6.13, N: 19.53.

Measured value -C: 50.27, H: 6.11, N: 19.49 δ7.46 (d, lH, J _5,6 = 1.2Hz, 6H), δ6.13 (t, 1H, 1'H) δ4.55-4.15 (M, 3H, 3′H, 5′CH ₂ ), δ3.8-4.15 (m, 1H, 4′H), δ2.4-1.78 (m, 3H, 2′H, 5′methine), δ1 .80 (d, 3H, J _5,6 = 1.2Hz, 5CH ₃ ), δ0.9 (d, 6H, J = 6.4Hz, 5'-methyl to butyryl) 3'-azido-3'-deoxy-5 ' -O-palmitoylthymidine calculated -C: 61.67, H: 8.57, N: 13.85.

Found -C: 61.85, H: 8.59, N: 13.75.

δ7.45 (d, lH, J _5,6 = 1.0Hz, 6H), δ6.12 (t, 1H, 1′H), δ4.5−4.05 (m, 3H, 3′H, 5′CH ₂ ), Δ4.0−3.8 (m, 1H, 4′H), δ2.35−2.11 (m, 4H, 2′H, palmitoyl (CH ₂ )
1), δ1.8 (d, 3H , J 5,6 = 1.0Hz, 5CH 3) δ1.35-0.6 (m, 29H, palmitoyl _{(CH 2) 13 CH 3)} 3'- azido-3'-deoxy -5-O-Toluylthydimine Calc'd-C: 56.10, H: 4.97, N: 18.17.

Found -C: 55.88, H: 5.00, N: 18.09.

Melting point: 73 ° C.

NMR measured in DMSO-d _6.

NMR-δ7.95-7.29 (m, 5H; bH, cH, 6H), δ6.16 (t, 1H, 1'H) δ4.6-4.4 (m, 3H, 3'H, 5'H), δ4.2-4.0 (m, 1H, 4'H) , δ2.39 (s, 3H, dCH 3), δ1.63 (s, 3H, 5CH 3) 3'- azido-3'-deoxythymidine -5 ′ -O-
(Hydrogen succinate) Calculated-C: 44.98, H: 4.83, N: 17.96.

Found -C: 44.90, H: 4.77, N: 17.85.

NMR measured in DMSO-d _6.

NMR-δ7.46- (s, 1H; 6H), δ6.13 (m, 1H, 1'H), δ4.48-4.40 (m, 1H, 3'H), δ4.34-4.20 (m, 2H, 5'H), δ3.99-3.94 (m , 1H, 4'H), δ1.78 (s, 3H, 5CH 3), 3'- azido-3'-deoxy-5'-mesyl-thymidine calculated Value-C: 38.25, H: 4.37, N: 20.28, C: 9.28.

Found -C: 38.15, H: 4.38, N: 20.19, C: 9.30.

Melting point: 253 ° C (decomposition).

NMR measured in DMSO-d _6.

NMR-δ7.49- (d, 1H, J _5,6 = 10Hz, 6H), δ6.15 (t, 1H, J _{1 ', 2'} = 6.6Hz, 1'H), δ4.54-4.41 ( m, 3H, 3′H, 5′H), δ4.14−4.02 (m, 1H, 4′H), δ3.24− (s, 3H, 5′-mesyl CH ₃ ), δ1.79 (d , 3H, J _5,6 = 1.0Hz, 5CH ₃ ) 3'-azido-5'-0- (3-chlorobenzoyl)-
Calculated value for 3'-deoxythymidine-C: 50.31, H: 3.97, N: 17.26, Cl: 8.74.

Found -C: 50.16, H: 4.03, N: 17.13, Cl: 8.66.

NMR measurement with DMSO.

NMR-δ 11.37 (s, 1H, 3-NH), δ7.98-7.43 (m, 5H; 5'-phenyl, 6H), δ6.17- (dd, 1H, J _{1 ', 2a'} = 6.1 Hz, J _{1 ', 2b'} = 7.2H
z, 1'H) δ4.68-4.48 (m, 3H, 3'H, 5'H), δ4.14-4.11 (m, 1H, 4'H), δ2.48-2.41 (m, 2H, 2'H), δ 1.64 (d, 3H, J _5,6 = 1.2Hz, 5CH ₃ ), Example 11 2,5'-0-anhydro-3'-azide-
3'-Deoxythymidine 3'-Azido-3'-deoxythymidine (3.0 g, 11.2 mMol) was mesylated by adding methanesulfonyl chloride (2.7 mL) to a solution of the starting material in dry pyridine (2 mL).
After reacting at 5 ° C for 1 hour, the mixture was poured into ice and the precipitate was collected by filtration. Product (3'-azido-5'-mesylthymidine)
Was reacted with potassium carbonate (0.78 g, 5.6 mMol) in DMF (75 mL). The reaction was heated in an 80 ° C. oil bath for 6 hours and then poured into ice water. The product was extracted from water with ethyl acetate, the solvent was removed in vacuo and the residual oil was subjected to flash chromatography on silica gel eluting with a mixture of CHCl ₃ : MeOH (9: 1 by volume). Evaporation of the solvent from the appropriate fractions and solidification gave the title compound.

Melting point 184-186 [deg.] C.

Example 12 3'-azido-3'-deoxythymidine (a) 2,3'-anhydrothymidine Thymidine (85.4 mg, 0.353 mol) was dissolved in 500 ml of dry DMF to give (2-chloro-1,1,2 -Trifluoroethyl) diethylamine (100.3 g, 0.529 mol) (DEAyer, Journal of Medicinal Chemistry, J. Med. Chem., 6, 608 (1963)) Added to. This solution was heated to 70 ° C. for 30 minutes and then poured into 950 ml of ethanol with vigorous stirring. The product precipitated from this solution was filtered off, the supernatant of ethanol was refrigerated, and then filtered to obtain the title compound.

Melting point 228-230 ° C.

(B) 3'-azido-3'-deoxythymidine 2,3'-O-anhydrothymidine (25 g, 0.1115 mol) and sodium azide (29 g, 0.446 mol) were added to 250 ml of DMF and 3
It was suspended in a mixed solution of 8 ml of water. The mixture was heated at reflux for 5 hours and then poured into 1 of water. The aqueous solution was added to EtOAc (3 x 700
ml), the extract was dried over Na ₂ SO ₄ , then filtered and the EtOAc removed in vacuo to give a viscous oil. 200 this oil
The mixture was stirred with ml of water to precipitate the title compound as a solid, and the solid was collected by filtration.

Melting point 116-118 [deg.] C.

Example 13 Monosodium salt of 3'-azido-3'-deoxythymidine Dissolve about 1 g of 3'-azido-3'-deoxythymidine in 50 ml of distilled water and adjust the pH to 12 with 1N NaOH.
Freeze drying about half of the solution to give the title compound as a chilled dry powder.

Analyzed as C ₁₀ H ₁₂ N ₅ NaO ₄ 6 / 10N ₂ O.

Calculated value -C: 40.03, H: 4.43, N: 23.34, Na: 7.66 Found value -C: 39.88, H: 4.34, N: 23.23, Na: 7.90 Example 14 Of 3'-azido-3'-deoxythymidine Preparation of 5'-monophosphate 3'-azido-3'-deoxythymidine (0.5 g, 1.87 mm
ol) was dissolved in 5 mL of triethyl phosphate, and the mixture was mixed with -5
Cooled to ° C. Phosphorus oxychloride (0.685 mL, 7 mmol),
After adding to the solution at once under rapid stirring,
I'll keep it for time. A part of the liquid was taken and added to concentrated aqueous ammonia.
This sample was applied to thin layer chromatography (cellulose, n-Pr
Analysis with OH / H ₂ O (volume 3: 7) confirmed that no starting material remained, and a simple fluorescent spot that was less mobile than the nucleoside was observed. The reaction mixture was poured into 20 mL of ice water, which was immersed in an ice bath and 2N NaOH was added to the solution to adjust its pH to 7.5. The basic mixture was extracted once with chloroform and once with ether. Adjust the pH of the aqueous layer to 7.
After adjusting to 5, concentrated in vacuo to remove residual organic solvent. The material was stored at -10 ° C for the next purification treatment.
First, cocoa coconut (50-200 mesh, 100g)
The deactivated chaicol was prepared by thoroughly rinsing with 1 N HCl (500 mL), water (3 L), 3% toluene in 95% ethanol (35 mL), 95% ethanol (600 mL), and finally water. Deactivated Chyacol (Deposited wet chacoal 12
mL) under stirring, monophosphate solution (0.72 g,
1.8 mmol, 30 mL). The supernatant was decanted and chalcol was washed with 150 mL of water, and chalcol was washed with a 1.5M 50% solution of ammonium hydroxide in ethanol to elute nucleotides. The solution was filtered through a 0.22μ filter, concentrated in vacuo to 10 mL, filtered through an Amicon Centriflo CF-25 membrane, freeze-dried and diammonium 3′-azide-3 ′.
-Deoxythymidine-5'-monophosphate was obtained as a solid. This compound is a nucleoside 5-which is converted into a nucleoside by a 5'-nucleotidase.
It had the characteristics of monophosphate.

Example 15 3'-Azido-5'-triphosphate-
3'-deoxythymidine and 3'-azido-5'-diphosphate-3'-deoxythymidine (a) bis (tri-n-butylammonium) pyrophosphate Dow 50 [Dowex ion exchange resin-Dow. [Chimical Laboratories] 40 mL of pyridinium resin was packed in a column having a diameter of 25 cm and washed with water until the color did not elute to prepare a resin column. Phosphate decahydrate (1.12 g, 2.51 mM) was dissolved in 30 mL of water and added to the column. Elute the column with water, UV
125 mL of the eluent fraction containing the substance that absorbs was collected. The liquid was concentrated to 10 mL under vacuum, and tri-n-butylamine (1.2 mL) was added. It was further concentrated in vacuo and the resulting residue was coevaporated 4 times with pyridine to dryness. The product was stored in a freezer at -5 ° C.

(B) 3'-azido-5'-monophosphate-3'-
Hydrogen form of deoxythymidine The ammonium salt obtained in Example 14 (0.1 g, 0.283 mMo
l) was dissolved in 6 mL water and passed through 1.5 mL (10 eq) Dow 50H ⁺ column to prepare the hydrogen form of the monophosphate.

(C) Phosphoromorpholidate of 3'-azido-3'-deoxythymidine The hydrogen form of the monophosphate obtained in step (b) (0.28
3mHol) was dissolved in 9mL of water. Morpholine (99 μL, 1.
After adding 13 mMol, 4 eq.) The solution was heated to reflux. te
Dicyclohexylcarbodiimide (0.234 g, 1.13 mMol, 4 eq) dissolved in rt-butanol (5 mL) was added over 3 hours and the reaction mixture was heated at reflux overnight then cooled to room temperature, filtered and the solvent removed. Removed in vacuo. Ethanol was added 4 times and evaporated each time. The residue was dissolved in methanol, and ether was added to precipitate phosphoromorpholidate. The precipitate was triturated with ether 4 times and dried on a rotary evaporator to give the title compound.

(C) The phosphoromorpholinate derivative obtained in step (c) was dried by removing pyridine 4 times in vacuo. The bis (n-Bu) ₃ N pyrophosphate obtained in step (a) was also dried by removing pyridine in vacuum. The phosphoromorpholidate was dissolved in 5 mL pyridine and added to the vessel containing the pyrophosphate reagent. After leaving the reaction mixture at room temperature overnight, the pyridine was removed in vacuo. Water was added to the residue and removed in vacuo three times. The residue was frozen.

The residue was then thawed and dissolved in 50 mL water. 50 mM solution
Was applied to a column (1 x 10 cm) of DEAE Saphadex A-25 equilibrated with ammonium bicarbonate. The phosphate was eluted with a 300 mL linear gradient of 50-800 mM ammonium bicarbonate. The fractions containing diphosphate nucleotides were pooled, and the triphosphate fractions were pooled as well. The pooled diphosphate and triphosphate fractions were each vacuum dried, redissolved in water, dried again, dissolved in water and freeze dried.

Example 16 3'-Azido-5'-triphosphate-
Enzymatic Synthesis of 3'-Deoxythymidine 5'-Triphosphate was synthesized from 5'-diphosphate using pyruvate kinase and nucleoside diphosphate kinase. The reaction mixture was 6 mM 3'-azide TDP,
12 mM adenosine triphosphate, 40 mM NgCl ₂ , 40 mM potassium piperazine-N, N'-bis (2-ethanesulfonic acid) PIPES buffer (pH 6.8), 30 mM phosphoenolpyruvate, 40 IU / ml Nucleoside diphosphate kinase, and 1
00 IU / ml pyruvate kinase was included in a final volume of 5 mL. The reaction mixture was kept at 37 ° C for 5 days and then equilibrated with ammonium bicarbonate DEAE Sephadex A-.
It was applied to 25 columns (2.5 x 10 cm). 1 nucleotide
Elution with a gradient of 00-1000 mM ammonium bicarbonate.
The fractions containing triphosphate were pooled and dried by vacuum evaporation. The compound is a preparative HPLC column (Whatman, Magnum 9 S
AX) for further purification, eluting with a gradient of 10-100 mM potassium phosphate, pH 3.5. The obtained compound is
It was further purified by a column of DEAE Sephadex A-25. 3'-azido-3'-deoxythymidine-5'-
Fractions containing tetraammonium triphosphate were pooled, vacuum dried, redissolved in water and freeze dried to give the title compound.

Example 17 Antiviral activity (a) (i) Retrovirus-induced toxicity 3'-Azido-3'-deoxythymidine
Of RVB3 strain of mouse (Rauscher Murine) leukemia virus
It was administered to BALB / C mice infected with 1.5 × 10 ⁴ pfu. Treatment started 4 hours after infection and every 8 hours 80 mg / Kg
Was intraperitoneally administered or orally added to drinking water at a concentration of 0.5 or 1.0 mg / ml. It was found that these treatments prevent the infection of splenocytes, the subsequent onset of splenomegaly, and the suppression of Viraemia.

(Iii) HTLV-I TM-II cells (T cell clones susceptible to HTLV-I infection) were co-cultured with irradiated HTLV-I producing MJ tumor cells as follows.

a) TM-II cells alone b) TM-II cells and MJ tumor cells c) TM-II cells, MJ tumor cells and 3'-azido-3'-
Deoxythymidine (3 μM) d) TM-II cells, MJ tumor cells and 3-azido-3-deoxythymidine (9 μM) e) TM-II cells, MJ tumor cells and 3-azido-3-deoxythymidine (27 μM) 18 On the day, total DNA was extracted from each culture and digested with BamHI to generate a fragment of the HTLV-I genome with a standard molecular weight of 3.3 kD, regardless of any host flanking order. The digest is Ba of HTLV-I
Radioactively labeled λMT- which is a standard probe for confirming mHI
Scrutinized with a 2.

No crosses were observed for a), indicating the absence of virus in uninfected controls. A strong signal was observed in the untreated infected control in case b). In case c) a weak signal was observed, indicating incomplete extinction of the virus. No crosses were observed in d) and e) indicating complete eradication of the virus.

Each culture medium was also probed for β-thiein, which is a T cell receptor, and it was observed that strong signals were emitted for all culture medium, and TM-II continued to exist for the duration of the experiment. Was showing that.

(B) AIDV (i) Reverse Transcriptase Activity 3'-Azido-5'-triphosphate-3'-deoxythymidine was tested in vitro against AIDV reverse transcriptase (AIDV RT).

AIDV RT was purified from pelletized and extracted AIDV by elution with DEAE and phosphocellulose columns. Enzyme activity was linear over 60 minutes and was stable for at least 2 months when stored in 60% glycerol and 1 mg / l bovine serum albumin. Using rA-odT _(12-18) as a template primer, AIDV RT
An optimal pH of 7.0-7.3, an optimal MnCl ₂ concentration of 0.3 mM, and an optimal MgCl ₂ concentration of 5 mM were kept. The activity in the presence of 5 mM MgCl ₂ was 10 times stronger than the activity in the presence of 0.3 mM. Maximum enzyme activity was found in the presence of 80-140 mM KCl and 60-100 mM NaCl.

[ ³ H] dTTP incorporation was linear with enzyme concentration. In a test, 3'-azido-5'-triphosphate-3'-deoxythymidine was found to be a competitive inhibitor of AIDV RT, using rA-odT _(12-18) as a template primer. When it showed a Ki of 0.04 μM. This enzyme has a Km of 2.81 μM dTTP and has a 3'-
It was shown that azido-5'-triphosphate-3'-deoxythymidine was more tightly bound to this enzyme than to dTTP. Avian myeloblastosis virus, Moloney murine leukemia virus and
From the experiment by RT of AIDV, it was found that 3'-azido-5'-triphosphate-3'-deoxythymidine is a terminator of DNA chain elongation.

(Iii) In Vitro Anti-AIDV Activity 3'-Azido-3'-deoxythymidine has been tested and shown to be active in a number of in vitro assay systems. The efficacy of the drug is as follows: Supernates from infected, uninfected, and drug-treated cells.
It was measured by the activity of reverse transcriptase (RT) in it. 3'-
Azido-3'-deoxythymidine is 2.7-0.0013 mcg / m
At a concentration of l, it effectively blocked AIDV infection of H9 and U937 human lymphoblastoid cell lines. Similarly, normal
PHA infection stimulated leukocytes and cultured peripheral blood lymphocytes were suppressed even at low drug concentrations of 0.013 mcg / ml. In experiments that add or subtract drugs in H9 cells,
3'-Azido-3'-deoxythymidine is most effective if it is present when susceptible cells are infected with the virus, but its application is delayed 20 hours after the first AIDV infection. It still retained most of its viral activity. Inhibition of viral replication was also clearly demonstrated when the drug was present in the vehicle only during the 20 hours of viral absorption. The effect was observed at concentrations of 0.13 and 0.013 mcg / ml. 3'-Azido-3'-deoxythymidine did not show direct anti-RT activity against purified AIDV virions. Similarly, the drug is a chronically infected H9ADIV
It had little or no effect on the production or release of virions from cell lines.

(Iii) Prevention of AIDV infection 3'-azido-3'-deoxythymidine cellular AIDV
The ability to prevent infection was tested as follows.

Cloned T4 positive tetanus specific T helper lymphocytes (at doses up to 5000 virions per cell) were infected with pools of AIDV sequestrants and post-infection cell viability was monitored. After 10 days of culture, the infected T cells treated with 8.8 and 1.3 mcg / ml of 3'-azido-3'-deoxythymidine showed no cytopathic effect of the virus, and untreated infected cells were
It has been reduced to 1/5. Cell viability of HTLV-I-transformed cells derived from the above cells in the AIDV co-infected cell line was also evaluated. In 7 days, 3'-azido-3'-deoxythymidine
The concentrations of 2.7, 0.27 and 0.13 mcg / ml completely blocked the cytopathic effect. Protective effects were seen in cell-free virions and cell-associated virus-induced infections. 3'-azido-3'-deoxythymidine is 0.27mc
AIDV's Haiti (Ha
It effectively prevented the induction of cytopathic effect by the isolate.

Example 18 Toxicity Assay 3'-Azido-3'-deoxythymidine was administered to mice and rats. LD ₅₀ value of 750 mg / Kg in both mouse and rat
That's all.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (31) Priority claim number 8603450 (32) Priority date February 12, 1986 (33) Priority claim country United Kingdom (GB) (72) Inventor Sandra Nusinof Railman Durham, North Carolina, USA , Old Scheuger Road 2720 (72) Inventor Martha Hader St. Clair, Durham, North Carolina, United States, Seven Oaks Road 312 (72) Inventor FIlipup Allen Farrman, Bruston Road, Durham, North Carolina, United States 901 (72) Inventor, Joey Andrew Freeman 107 Carouts Drain, Carrie, North Carolina, United States

Claims (16)

[Claims] 1. Treating or preventing a human retroviral infection comprising as active ingredients a pharmaceutically acceptable 5'-salt or ester of 3'-azido-3'-deoxythymidine and a pharmaceutically acceptable carrier. A pharmaceutical composition for. 2. A carrier according to claim 1, wherein the carrier is other than water.
The composition according to the item. 3. A composition as claimed in claim 1 or claim 2, which is sterilized. 4. The composition according to claim 3, which is suitable for administration by injection. 5. The composition according to claim 4, which is contained in a sealed vial. 6. The composition according to claim 1, wherein the carrier is sterile water. 7. The composition according to claim 1, which is suitable for oral administration. 8. The pharmaceutical composition according to claim 1, which is a tablet or capsule containing a pharmaceutically acceptable 5'-salt or ester of 3'-azido-3'-deoxythymidine. 9. The composition according to claim 8, wherein the active ingredient can be sustainedly released after oral administration. 10. The composition according to claim 7, which contains a seasoning agent. 11. The composition according to any one of claims 1 to 10, which contains the active ingredient in a unit dose or a multiple dose thereof. 12. The composition according to claim 11, wherein the unit dose of the active ingredient is 20 to 700 mg. 13. A composition according to any one of claims 1 to 12 for the treatment or prevention of acquired immunodeficiency virus (AIDV) infection. 14. A composition according to any one of claims 1 to 13 for the treatment or prevention of AIDS. 15. The composition according to any one of claims 1 to 13 for treating or preventing HTLV-I infection. 16. A 3'-azido-3'-other than the following 5'-esters: monophosphate, disodium monophosphate, 2-cyanoethyl monophosphate, triphosphate, p-toluene sulfonate, acetate or methane sulfonate. A pharmaceutically acceptable 5'-salt or ester of deoxythymidine.